TRP Channels and Air Pollution

TRP 通道和空气污染

• 批准号: 8513989
• 负责人: Christopher A Reilly
• 金额: $ 32.85万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513989
• 关键词: Acute; Address; Adverse effects; Affect; Afferent Neurons; Agonist; Air; Air Pollution; Apoptotic; Arbitration; Attenuated; Benzene; Biological Assay; Caring; Cell Surface Receptors; Cells; Chemicals; Chronic; Chronic Disease; Clinical Treatment; Coal; Collection; Complex; Cytochrome P450; Data; Development; Diesel Exhaust; Epithelial Cells; Event; Functional disorder; Genes; Goals; Health; Homeostasis; Human; Image; Individual; Inflammatory; Interleukin-6; Interleukin-8; Interleukins; Intervention; Investigation; Ion Channel; Ion Channel Protein; Knockout Mice; Link; Literature; Lung; Lung Compliance; Mechanics; Mediating; Mediator of activation protein; Medical; Metalloproteases; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NADP; NQO1 gene; Neurokinin A; Neurons; Particulate; Pathology; Pathway interactions; Persons; Physiological; Population; Proteins; Public Health; Receptor Inhibition; Research; Research Project Grants; Respiratory physiology; Risk; Shapes; Site; Smoke; Somatostatin; Structure of parenchyma of lung; Substance P; Substance P Receptor; Surface; TRP channel; TRPA1 Channel; TRPV1 gene; Techniques; Testing; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; Variant; Wood material; adverse outcome; base; cDNA Arrays; chemical release; clinically relevant; effective therapy; environmental particulate; fascinate; fly ash; functional group; gene induction; improved; innovation; lung injury; mutant; particle; particle exposure; particulate pollutant; population based; preprotachykinin A; prevent; programs; protein expression; receptor; respiratory; response; sensor; therapeutic development; therapeutic target

DESCRIPTION (provided by applicant): The long-term goal of our research is to improve care of persons adversely affected by particulate components of air pollution (PM) by elucidating specific molecular pathways that mediate adverse respiratory responses to PM. The immediate goals of this project are to establish the molecular and chemical basis for differential activation of the recently discovered "PM-sensing" Ca++ channels, TRPA1, V1, and M8, using two representative combustion-derived particles (cdPM): diesel PM (DEP) and coal fly ash (CFA1), to reveal the contributions of these ion channels in determining PM-induced changes in airway cell homeostasis and respiratory function. Our hypothesis is: TRPA1, V1, and M8 are differentially activated by cdPM as a function of its physical/chemical composition, receptor-specific chemo- and mechano-sensing domains, and cellular expression/localization of TRPA1, V1, and M8 channels. Furthermore, activation of TRPA1, V1 and/or M8 by cdPM are pivotal events underlying the pneumotoxic effects of DEP, CFA1, and similar environmental cdPM. Our specific aims are: 1) pinpoint the regions of TRPA1, V1, and M8 required for activation by DEP and CFA1; 2) link TRPA1, V1, and/or M8 activation with specific airway cellular responses to DEP and CFA1; and 3) demonstrate TRPA1, V1, and/or M8 as mediators of pathophysiological responses of lung tissue to DEP and CFA1. The hypothesis and aims of this study are based on fascinating results showing that several PM, including DEP and CFA1, interact with these specific ion channel proteins at the surface of lung cells, and through unique pharmacological mechanisms, regulate discrete cellular and lung responses that underlie commonly observed PM-induced pulmonary morbidities. Our supporting data demonstrate TRPA1 is predominantly, but not exclusively, activated by reactive chemicals released from DEP and another environmentally relevant cdPM; wood smoke PM (WSP), while TRPV1, M8, and to a lesser extent A1, are uniquely activated by mechanical perturbation of cell surface receptor domains by insoluble components of DEP, CFA1, and other model PM. Neuronal stimulation and subsequent reduction in lung compliance elicited by DEP are inhibited by the TRPA1 antagonist HC-030031, and both neurons and bronchial epithelial cells are stimulated by CFA1 via TRPV1, with pro-inflammatory and pro-apoptotic gene induction in lung epithelial cells and lung tissue being largely dependent upon TRPV1 expression and function (i.e., inhibited by the antagonist LJO-328 or in TRPV1-/- mice). Upon completion of the proposed studies, we will provide conclusive evidence that TRPA1, V1, and M8 are specific molecular pathways that link air pollution to commonly observed adverse outcomes in respiratory tissue. This information is essential for both identifying highly sensitive individuals at greatest risk for developing health problems due to air pollution and developing innovative clinical treatments to protect such people from the adverse effects of PM.

描述（由申请人提供）：我们研究的长期目标是通过阐明介导对 PM 的不良呼吸反应的特定分子途径，改善对受到空气污染 (PM) 颗粒成分不利影响的人员的护理。该项目的直接目标是建立差异激活的分子和化学基础 最近发现的“PM 传感”Ca++ 通道 TRPA1、V1 和 M8，使用两种代表性的燃烧衍生颗粒 (cdPM)：柴油 PM (DEP) 和煤飞灰 (CFA1)，揭示这些离子通道在确定 PM 引起的气道细胞稳态和呼吸功能变化中的贡献。我们的假设是：TRPA1、V1 和 M8 被 cdPM 不同程度地激活，与其物理/化学成分、受体特异性化学和机械传感域以及 TRPA1、V1 和 M8 通道的细胞表达/定位有关。此外，cdPM 对 TRPA1、V1 和/或 M8 的激活是 DEP、CFA1 和类似环境 cdPM 的肺毒性作用的关键事件。我们的具体目标是：1）查明 DEP 和 CFA1 激活所需的 TRPA1、V1 和 M8 区域； 2) 将 TRPA1、V1 和/或 M8 激活与对 DEP 和 CFA1 的特定气道细胞反应联系起来； 3)证明TRPA1、V1和/或M8是肺组织对DEP和CFA1病理生理反应的介体。本研究的假设和目的基于令人着迷的结果，这些结果表明，包括 DEP 和 CFA1 在内的多种 PM 与肺细胞表面的这些特定离子通道蛋白相互作用，并通过独特的药理学机制，调节离散的细胞和肺部反应，这些反应是常见的 PM 引起的肺部疾病的基础。我们的支持数据表明，TRPA1 主要但并非完全由 DEP 和另一种与环境相关的 cdPM 释放的反应性化学物质激活；木烟 PM (WSP)，而 TRPV1、M8 和较小程度的 A1，则通过 DEP、CFA1 和其他模型 PM 的不溶性成分对细胞表面受体域的机械扰动而独特地激活。 DEP 引起的神经元刺激和随后的肺顺应性降低被 TRPA1 拮抗剂 HC-030031 抑制，CFA1 通过 TRPV1 刺激神经元和支气管上皮细胞，肺上皮细胞和肺组织中促炎和促凋亡基因的诱导很大程度上依赖于 TRPV1 的表达和功能 （即被拮抗剂 LJO-328 或 TRPV1-/- 小鼠抑制）。完成拟议的研究后，我们将提供确凿的证据，证明 TRPA1、V1 和 M8 是将空气污染与呼吸组织中常见不良后果联系起来的特定分子途径。这些信息对于识别因空气污染而面临健康问题风险最大的高度敏感个体以及开发创新的临床治疗方法以保护这些人免受颗粒物的不利影响至关重要。